Information integration is rapidly becoming a severe bottleneck in biomedical science as researchers grapple with complex disease processes and rapidly increasing data volumes. The University of Michigan will establish a National Center for Integrative Biomedical Informatics (NCIBI) to meet this challenge and thereby advance the study of complex, clinically significant biomolecular systems. The Center will develop problem-posing computational architecture within a managed software and data infrastructure that will permit the facile manipulation and analysis of today's massive data sets. This architecture exploits scalable and flexible software technology and enables component reuse and re-organization. The Center's knowledge environment implements full provenance tracking for information, and thus enables users to 'drill-down'to primary source data and to appropriately cite data providers. With this infrastructure, an integrative modeling and hypothesis-testing resource will be created, drawing on public databases, high-throughput experimental data, and literature resources. Biological knowledge environments, improved ontologies and advanced tools for information retrieval will be developed to use with this integrated knowledge base. These environments will enable the analysis and modeling of complex and dynamic biomedical systems, and in time will allow the integration of biomedical and behavioral data at multiple levels of organization. The NCIBI will demonstrate and challenge these technologies with four driving biological projects in Type I and Type II diabetes, prostate cancer and the genetics of bipolar disorders. We will facilitate community access, collaborative activities, and data sharing in the Center, and freely disseminate tools and web-based services for biomolecular data analysis. The NCIBI will establish innovative education and training programs leveraging the integrated information resource. Intrinsic to the Center will be a secure computational infrastructure to support its activities. Administrative structures will be established to manage and sustain the Center. An Intellectual Property and Data Sharing Committee will set and modify data and software dissemination and use policies. The NCIBI Executive Committee will review and recruit new Driving Biological Projects (DBPs). The Center will be overseen by the Co-PIs and a professional project manager.